Cardiovascular Effects

Clin. Cardiol. 11, 253-260 (1988)

Cardiovascular Effects of Berberine in Patients with Severe Congestive Heart Failure”

J . A. MARIN-NETO, M.D., D. Sci., B. c. MACIEL, M.D., A. L. SECCHES, M.D., L. GALLO Jr., M.D.

Cardiac catheterization Laboratory, SeCb de Hemodinlmica e FunCiio Pulmonar, Hospital das Clinicas da Faculdade de Medi- cina de Ribeifio Preto, University of S b Paulo

Summary: Berberine, an alkaloid of the protoberberine family, has been shown to have strong positive inotropic and peripheral resistance-lowering effects in dogs with and without heart failure. To determine the acute cardiovascular effects of berberine in humans, 12 patients with refractory congestive heart failure were studied before and during berberine intravenous infusion at rates of 0.02 and 0.2 mg/kg per min for 30 minutes. The lower infusion dose produced no significant circulatory changes, apart from a reduction in heart rate (14%). The 0.2 mg/kg per min dose elicited several significant changes: (a) Decreases in systemic (48%, p<O.Ol) and pulmonary vascular resistance (41%, p<O.Ol), and in right atrium (2896, p < 0.05) and left ventricular enddiastolic pressures (32 % , p<O.Ol). (b) Increases in cardiac index (45%, p<O.Ol), stroke index (45%, p<O.Ol), and LV ejection fraction measured by contrast angiography (56%, p<O.Ol). (c) Increases in hemodynamic and echocardiographic indices of LV performance: peak measured velocity of shorten: ing (45%, p <0.01), peak shortening velocity at zero load (41 %, p <0.01), rate of development of pressure at developed isovolumic pressure of 40 mmHg (20%, p<O.Ol), percent fractional shortening (50%, p<O.Ol), and the mean velocity of circumferential fiber shortening (5496, p<O.Ol). (d) Decrease of arteriovenous oxygen difference (28 % , p < 0.05) with no changes in total body oxygen uptake, arterial oxygen tension, or hemoglobin dis-

*Supported by Grant med. 83/2162-0 from the FundacSo de Am- paro h Pesquisa do Estado de S b Paulo (FAPESP), Brazil.

Address for reprints:

Jose A. Marin Neto, M.D., D.Sci. Cardiac Catheterization Laboratory Faculdade de Medicina de Ribeirfio Preto

Received: July 28, 1987 Accepted: September 14, 1987

14048 - Ribeirrio Preto, SP, Brad

sociation properties. These salutary acute effects show that berberine markedly improved cardiac performance in patients with heart failure refractory to conventional medical therapy with digitalis and diuretics. The improvement is probably subsequent to peripheral vasodilatation and to inotropic stimulation. Significant untoward effects appear to be the development of ventricular tachycardia with “torsades de pointes” morphology, detected in 4 patients 1- 20 h after the infusion of berberine. This possible association requires further elucidation before the administration of bekrine may be extended to other patients in heart failure.

Key words: berberine, vasodilatation, inotropism, heart failure, torsades de pointes, anhythmogenicity of antiarrhythmic agents

Introduction

Many pharmacological classes of vasodilators have been examined extensively over the current and the last decades. Numerous investigations have demonstrated that such agents primarily reduce ventricular loading conditions, thus inducing correspondent increases in stroke volume and cardiac output. Also, a variety of new positive inotrop ic agents are being investigated, as a therapeutic measure directed to correct the intrinsic decrease of cardiac contractility seen in many patients with congestive heart failure.

It may be proposed that a drug that can directly increase contractility and, at the same time, reduce peripheral resistance will be of obvious therapeutic advantage for the treatment of heart failure. Berberine (BBR) (Fig. 1) is one of a series of protoberberine alkaloids devoid of digitalis- like or adrenergic properties,’ that has been shown to lower peripheral vascular resistance and ~ t imula t e~-~ cardiac inotropism in dogs with and without heart failure. In addition, it has also been shown to antagonize experimentally induced cardiac dysrhythmias in animal models such as

254 Clin. Cardiol. Vol. 11, April 1988

FIG. 1 Chemical structure of berberine, one of the protoberberine alkaloids.

aconitine and digitalis intoxication in dog^,^.^ or coronary occlusion in rats.’ Because of its ability to reduce ventricular afterload and augment myocardial contractility, BBR appears to be potentially useful in congestive heart failure. We examined the acute hemodynamic responses to intravenous BBR infusions in subjects with refractory chronic congestive heart failure, being subjected to diagnostic cardiac catheterization procedures.

Methods

Patient Population

Twelve patients (2 female, 10 male) with severe congestive heart failure (CHF), refractory to conventional medical treatment were studied after institutional approval and informed consent was obtained. The investigation was in accordance with the Declaration of Helsinki. The mean age was 47.8 years (range 27 to 66). Etiologic diagnosis was chronic Chagas’ cardiopathy in 6, idiopathic dilated cardiomyopathy in 4, ischemic heart disease in 1, and chronic rheumatic aortic regurgitation in the last patient. Six patients were categorized as functional class III and the remaining 6 were placed in class IV according to the New York Heart Association Classification (1964). All patients studied were receiving a daily digoxin dose of 0.25 mg orally and furosemide (daily oral dose range 40 to 160 mg). In addition, 2 patients were on spironolac- tone (daily oral dose 100 and 200 mg, respectively). All patients had previously received vasodilators or a converting-enzyme inhibitor; these drugs were discon- tinued at least 48 hours before the study. The digitalis and diuretics administration was maintained unaltered through- out the period of study, as was antiarrhythmic therapy based on amiodarone (600 mg daily, in 2 patients) and disopyramide (200 mg daily, in 2 patients).

Study Design

Patients were hospitalized for at least 3 days before catheterization, to ensure a stable medical regimen and

diet. All studies were carried out in the afternoon, in a postprandial condition following a light meal, without premedication.

After routine diagnostic coronary and left ventricular cineangiography with Hypaque 75% (30 ml at 10 ml/s), about 20 minutes supine rest was allowed for return to the basal state.8 Hemodynamic, oxymetric, and echocardiography measurements were then camed out for baseline condition, followed by a 30-min intravenous infusion period of berberine at the rate of 0.02 mg/kg per min, with an increment to 0.2 mg/kg per min for an additional period of 30 minutes. At each period, the hemodynamic measurements were repeated. At the end of the period of the higher infusion rate, echocardiographic, and oxymetric determinations were performed again, and a second injection of contrast was done for selective left cineangiography (same technique as for the first injection).

Measurements

Right and left-sided cardiac catheterization was performed after cut-down in the right antecubital fossa un- der local anesthesia. Selective coronary arteriography was performed, followed by left ventricular cineangiography through a Sones 8F catheter. This catheter was thereafter replaced by a #7F Millar tip-micromanometer, which was positioned across the aortic valve, to measure pressures in the left ventricle and aorta simultaneously. A triple- lumen flow-directed catheter was used for measurement of pressures in the pulmonary circulation and right heart, as well as for determination of cardiac output by thermodilution. Injections of 10 ml cold solution were effected in triplicate (5 injections if variation exceeded lo%), using a model DTCCO-07 Electronics for Medicine Honeywell cardiac output computer. The electrocardiogram, the ana- logic output of thermodilution curves, pressures, and the first derivative of left ventricular pressure were displayed on a Hewlett-Packard 8890-B multichannel recorder, stored on magnetic tape and processed by computer. In- dices of left ventricular contractility, including peak + dP/dt, the peak measured velocity of the contractile ele- ment (VPM), the peak shortening velocity at zero load (Vmax), and the rate of development of pressure at the developed isovolumic pressure of 40 mmHg (dP/dt/DP40) were derived by on-line computer processing of the pressure signal, according to standard calculation^.^

Systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were calculated (dyne-sar’) from the following formulas: SVR= 80 x (mean aortic pressure - mean right atrial pressure)/cardiac output and PVR = 80 x (mean pulmonary pressure - mean wedge pressure)/cardiac output.

Expired air was collected in 3 minute periods and passed through a Beckman metabolic measurement cart, permit- ting determination of oxygen uptake (VO,) and C 0 2 production. Arterial and mixed venous (pulmonary artery) samples were drawn for determination of oxygen content

J. A. Marin Net0 et al .: Berbenne in human heart failure 255

in a Coming 175 Gas Analyser, and calculation of the arteriovenous oxygen difference (AA-V02); in addition, a Hemo-0-Scan Aminco Analyser was used to draw the hemoglobin dissociation curve for each patient, allowing the determination of the arterial pressure at which the saturation was 50% (P50).

Left ventricular ejection fraction was measured by the single-plane method of Sandler and Dodge,Io by means of a Vanguard motion analyzer.

Two-dimensional echocardiography was camed out with a Hewlett-Packard 77020 A imaging system, per- mitting the measurement of end-diastolic and end-systolic left ventricular dimensions, and the calculation of the percent fractional shortening (AD%) and of the mean circumferential fiber shortening velocity (VCF).

Statistical Analysis

The significance of the acute effects of both infusion rates, as compared to baseline values, was assessed by a paired Student's t-test. Significance of data was deter- mined at the level of p<O.O5.

Results

Control and postberberine hemodynamic, echocardiographic, and oxymetric measurements (mean f SD) are presented in Tables I to III. Figures 2 to 6 also depict individual behavior of several circulatory parameters for baseline condition and after the infusion rate of 0.2 mg/kg/min of berberine.

Control measurements showed severe left ventricular dysfunction, with low cardiac output, high arteriovenous oxygen difference, and increased vascular resistances.

The first infusion rate (0.02 mg/kg/min) failed to induce significant circulatory changes, with the exception of a modest decrease in heart rate, from 89.6f 18.1 to

c z 'g 2

2

Fj 0

77.3f19.1 beatdmin (-14%, pc0.05). The infusion of bekrine at the rate of 0.2 mg/kg per min

was associated with profound circulatory alterations. The i

$

heart rate returned to near baseline values (89.9f28.0 beatslmin). As compared to control condition, there was a significant fall in all cardiovascular pressures measured:

C 0 0

rightatrium, from 13.0f7.6to9.3*7.0mmHg, -28%, p<0.05; pulmonary wedge, from 21.7f7f7.0 to 16.2f6.0 mmHg, -25%, p<O.Ol; pulmonary artery, from 30.5 f9.6 to 25.1 f9.2 mmHg, - 18%, p cO.01; left ventricular end-diastolic, from 21.0f10.8 to 14.2f5.4 mmHg, - 32 % , p < 0.01 ; mean aortic, from 98.1 f9.9 to

Significant increases were produced in cardiac index (from 2.2f0.9 to 3.2f0.9 l/min/m2, +45%, pCO.Ol), stroke index (from 24.5f11.9 to 35.6f14.6 ml/m2, +45%, p<O.Ol), and left ventricular stroke work index (from 33.9f16.8 to 39.1f16.0 g.min/m2, +15%, pc0.05)

8

8 5 c) ._ C h 0 ,A

V

85.4f9.7 mmHg, - 13%, pCO.01 (Table I and Fig. 2). Y

G c1

w A m (Table I and Fig. 3). A significant decrease was seen in sys- ;1"

256 Clin. Cardiol. Vol. 1 1 , April 1988

TABLE I1 Effects of berberine on isovolumic-phase indices of left ventricular performance

Peak (+) dP/dt VPM ",X dP/dt/DP 40

Control 1089 f 2 10 1.07f0.42 1.26f0.40 18.9f2.7 Berberine (0.02 mg/kg/min) 1075 f240 1.16f0.41 1.40f0.47 19.5f2.9 Berberine (0.2 mglkglmin) 1203f289" 1 S5f0.56 1.78 f0.56" 22.6 f4.5'

' <0.01. Abbreviations: Peak (+) dP/dt=maximum positive first time derivative of left ventricular pressure (mmHg/s); VPM =left ventricular peak measured shortening velocity (circ/s); V,,, =maximum left ventricular shortening velocity (circk); dP/dt/DP 40 =value of the rate of development of pressure at the developed isovolumic pressure of 40 mmHg (s-I).

TABLE III Effects of intravenous berberine on echocardiographic variables and oxymetric characteristics

n= 12 LVDd LVDs AD % VCF vo2 PaOz AA-VO2 p50

Control 65.Jf8.8 53.7f8.5 18.3f4.0 0.70f0.17 224563 76.4f 10.3 6.53f2.47 28.7f2.75 Berberine (0.2 mglkglmin) 65.0f9.4 47.3f9.3' 27.5f5.7' 1.08f0.25b 241f61 71.9f9.2 4.73f1.52' 27.5f2.28

"p <0.05.

Abbreviations: LVDd =left ventricular end-diastolic dimension (cm); LVDs =left ventricular end-systolic dimension (cm); AD % =percent fractional shortening; VCF=mean circumferential fiber shortening velocity (circ/s); VOz =oxygen uptake (mllrnin, STPD); PaO, =arterial oxygen tension (mmHg); AA-VO2 =arterial venous oxygen difference (ml/ 100 ml); Ps0=arterial oxygen tension for saturation 50%.

bp<O.Ol*

I 80 lo0l

i c B

I SVR (dyne*s*cm-')

4 0 0 0 t h

1000 I=%=

LVEDP-(mmHg) F 4 0 c \

1 PVR (dyne*s*cm-5)

15001 \

FIG. 2 Individual changes in mean aortic pressure (AoP), left ventricular end-diastolic pressure (LVEDP), systemic (SVR) and pulmonary vascular resistance (PVR) from control (C) to the end of the 30-min period of 0.2 mg/kg/min infusion of berberine (B). Bars indicate mean values, for the group. p<O.OI, for all parameters.

9

4.0

2.0

AD% k-- f g m

20 'i - " I

12t7--- I

VcF-(circls)

1.4

FIG. 3 Individual changes in cardiac index (CI), systemic arteriovenous oxygen difference (AA -V02), percent fractional shortening (AD%), and mean velocity of circumferential shortening (VCF), from control (C) to the end of 30 minute period of 0.2 mglkglmin infusion of berberine (B). Bars indicate mean values for the group. p<O.OI for all parameters.

J. A. Marin Net0 et al.: Beherine in human heart failure

80

60

40

20

257

7

-

-

-

-

F 0.5

0 .3 Im&

0 4 - c 6

1400p3 I000

600b c r-

FIG. 4 Individual changes in left ventricular ejection fraction (EF), the maximum rate of rise of left ventricular pressure (peak + dP/dt), the peak shortening velocity at zero load (V,,,), and the rate of development of pressure at the developed isovolumic pressure of 40 mmHg (dP/dt/DP 40), from control to the end of the 30-min of 0.2 mg/kg min infusion of berberine (B). Bars indicate mean values for the group. p<O.O1 for all parameters.

~ ~~ ~

10 20 30 ~ 40 50 LVEDP (rnmHg)

FIG. 5 Relationship between left ventricular end-diastolic pressure (LVEDP) and stroke index (SVI). Dots are control values and ar- rowheads are values at the end of the 3 0 4 1 1 period of 0.2 mg/kg/min infusion of berberine.

temic vascular resistance (from 2667 f 1064 to 1384 f459 dyneeu~crn-~, -48%, p < 0.01) and pulmonary vascular resistance (from 745 f293 to 441 f250 dyne-scm-s, -41%, p<O.Ol) (Table I and Fig. 2). Left ventricular ejection fraction was elevated from: 0.27f0.07 to 0.42fO.11, +56%,p<0.01 (TableIandFig.4).Atypi- cal case is illustrated in Figure 6, showing end-diastolic and end-systolic frames before and after behrine . The left ventricular indices of contractility were also significantly increased after the infusion of 0.2 mg/kg per min of berberine (Table I1 and Fig. 4): Peak+dP/dt from 1089f210 to 1203f289 mmHg/s, +lo%, pc0.01; VPM, from

FIG. 6 Left ventriculographic response to 0.2 mg/kg/min infusion of berberine for 30 min. A representative case of Chagas’ cardiac failure is shown. Panels at left represent end-diastolic frames, before (upper) and during berberine (lower). Right panels correspond the end-systolic frames respectively. Ejection fraction was 0.25 in control, and 0.43 during berberine condition.


1.07f0.42 to 1.55f0.56circ/s, f45%, p<O.Ol; V,,, from 1.26f0.40 to 1.78f0.56 circ/s, +41%, p<O.Ol; dP/dt/DP 40, from 18.952.7 to 22.6f4.5 .s-I, +20%, p<O.Ol. Improvement in left ventricular performance is also shown by increases in echocardiographic measurements of AD% (from 18.3k4.0 to 27.5f5.7, +50%, p <0.01) and VCF (from 0.7 fO. 17 to 1.08f0.25 circ/s, +54%, p<O.Ol) (Table I11 and Fig. 2) as well as by the shift to the left and upward in the relationship between left ventricular filling pressure and stroke volume index (Fig. 5). Table I11 also shows that the V02, the PaOz and the Pso were not significantly affected by berberine, while an important reduction was noticed in AA - V 0 2 (from 6.53f2.47 to4.73fl .53 ml/dl, -28%, p<0.05) (Fig. 3).

Side Effects

Facial flushing was seen in 2 cases. In two others, tran- sient nausea was experienced within one hour after the end of infusion of berberine. In 4 patients, repetitive episodes of sustained ventricular tachycardia of the type “torsades de pointes” occurred between 1 and 20 hours after the end of the infusion. No predisposing factor to this com- plication was detected in these 4 patients regarding age, etiology ( 2 with idiopathic dilated cardiomyopathy, 1 ischemic, and 1 chronic Chagas’ heart disease), and severi- ty of cardiac failure (3 in class 111), electrolyte status, digoxin levels, or previous use of antiarrhythmic drugs (in only 2 cases: amiodarone in one and disopyramide in the other). On the other hand, the QT interval corrected for heart rate (QT,) was consistently increased following berberine administration in all patients. In the group without arrhythmic side effects, the QT, increased from 0.42 (0.34-0.50) in baseline condition to 0.48 (0.40-0.59) after berberine. In the 4 patients who developed VT, the QT, increased from 0.38, 0.52, 0.46, and 0.43 in baseline, to, respectively, 0.50, 0.59, 0.55, and 0.58 during the hemodynamic determinations after berberine infusion at the rate of 0.2 mg/kg per min. In 4 patients of the group without VT in whom the QT, was evaluated 12 h after the berberine infusion, its value was: 0.46, 0.56, 0.56, and 0.50. In the patients who had VT, the QT, was still excessively prolonged 12 h after the cessation of berberine infusion: 0.60, 0.70, 0.66, 0.64. No other ECG changes were seen in either group.

Clinical control of the ventricular tachycardia was achieved in all cases by cardioversion and isoproterenol administration. A remarkable hemodynamic stability was observed during the VT episodes, even though these patients had striking curtailment of cardiovascular reserve in baseline condition. The QT, interval was gradually reduced, returning to baseline values around 24 h after the infusion of barberine.

All patients studied had otherwise uneventful discharge from the hospital a few days after the cardiac catheterization date.

Discussion

The goal of this investigation was to examine the acute hemodynamic effects of intravenous BBR administration in patients with refractory chronic congestive heart failure. Our results indicate that BBR evoked significant hemodynamic effects in these patients, at the infusion rate of 0.2 mg/kg per min. A marked reduction in systemic and pulmonary vascular resistance, coupled with increased cardiac output, resulted in significant decreases in both systemic and pulmonary arterial pressures. The filling pressures of both ventricles were lowered, and such reduction was associated with increased stroke index, showing a shift in the Frank-Starling curve upward and to the left. Further evidence of improvement in cardiovascular function is shown by favorable BBR effects on several hemodynamic and echocardiographic indices of left ventricular performance. Correspondent with the increase in cardiac output elicited by BBR, an important reduction was detected in the systemic arteriovenous difference of oxygen content.

The hemodynamic improvement in these patients during BBR administration is probably due to an effective unloading of both ventricles combined with stimulation of the inotropic state of the myocardium. Arteriolar vasodilatation was certainly responsible for the drop in systemic pressure and resistance during BBR. Although no significant changes in ventricular diastolic volumes could be detected by angiographic or echocardiographic methods, a major salutary decreasing effect on ventricular afterload was surely induced by BBR, due to diminished vascular resistance, and ventricular pressure- volume values during systole. That this, in fact, was the case is shown by a decrease in left ventricular systolic dimension and by the increase in left ventricular ejection fraction. On the other hand, a possible direct venodilator effect of BBR cannot be ascertained from this study, because no attempt was made to measure capacitance in venous beds. Nevertheless, a beneficial effect of BBR on preload conditions was evoked, at least in terms of the marked decreases in ventricular filling pressures that were correspondent to significantly reduced systemic and pulmonary venous pressures. Finally, the changes in the indices of inotropism, as measured during both the isovolumic and the ejection phases of contraction, suggest a modification of the contmctile state of the myocardium during BBR administration. It is known that such indices can be influenced by concomitant changes in heart rate, preload, and afterload11-14 conditions. However, it should be noted that no change in heart rate was seen, and that a reduction in ventricular filling pressure, as measured during BBR, should tend to decrease, instead of increase the isovolumic phase indices of performance. Furthermore, the hypothesis of a positive inotropic effect during BBR is cor- roborated by the fact that some isovolumic phase indices (e.g., the rate of development of pressure at the developed isovolumic pressure of 40 mmHg) are quite insensitive to

J. A. Marin Net0 et al. : Berberine in human heart failure 259

afterload changes. Whether the change in inotropic state is due to direct effects of BBR (as suggested by the evidence from animal experiment~~-~) or reflex stimulation elicited by the drop in arterial pressure, cannot be ascertained in the conditions of the present study. On the other hand, in vitro studies with isolated vascular smooth muscle would need to be performed to assess direct vasodilating properties of berberine. Also, the relative vasodilator versus inotropic effects should be further elucidated by comparison, in the same patients, of changes induced in vascular resistance and in the indices of contractility by pure ino- tropes such as dob~tamine’~ or pure vasodilators such as nitroprusside.

Apart from defects of alveolar ventilation, perfusion, and diffusion, many patients in heart failure have the potential for venous admixture disturbances. I 6 . l 7 Moreover, the po- tent vasodilators often used in this context may produce deleterious effects because of further increase in the net physiologic right-to-left shunt, thus leading to reduced systemic arterial In our patients, BBR aug- mented the oxygen transport, because no changes were detected in arterial oxygen tension (PaO,) or in the hemoglobin-oxygen binding characteristics (Pso), but cardiac output was increased. However, it may be concluded that BBR does not cause increased ventilation-perfusion matching abnormalities, nor does it induce overriding of local hypoxic vasoconstriction in the lungs, at least in resting conditions. Whether this would hold true during exer- cise remains to be elucidated in subsequent studies.

Future experimental and clinical studies need also to de- fine whether the occurrence of ventricular tachycardia of “torsades de pointes” type in 4 of our patients was due to electrophysiological effects of berberine. In normal dogs, anesthetized with morphine-pentobarbital, no significant effects were noticed in depolarization or conduction properties of atrial, junctional, and ventriculartissues, in a study being carried out in our laboratory. In addition, we did not perform Holter monitoring of patients before and after BBR administration, to check if sustained ventricular arrhythmias were already present in baseline condition. However, BBR does appear to have antiarrhythmic effects,2.6.7 in animal models. Thus, it may be reasoned that BBR could possess the potential for aggravation or provocation of ventricular arrhythmias, as shown by evidence from studies with other antiarrhythmic drugs.Z0-22 This important point should be scrutinized carefully before the use of BBR can be recommended for patients in heart failure for its promis- ing effects on ventricular performance and peripheral resistance. Further studies are now in progress in our laboratory, exploring possible electrophysiological actions of BBR on the repolarization properties of the canine myocardium. It should be stressed that the mechanisms pos- sibly responsible for the actions of berberine upon the contractile state and vasoregulation are still unknown. In a re- cent study of isolated guinea pig atrial tissue, it has been suggested that berberine enhancement of the force-velocity relationship and of the duration of the active state may be

due to alteration in transsarcolemmal flux of calcium and inhibition of intracellular calcium sequestration system.23 On the other hand, inhibition of rat acetylcholinesterase has been postulated as a contributory factor to the hypotensive action of berberine.24

Acknowledgments

We are grateful to Professor SCrgio H. Ferreira (Phar- macology Department, Medical School of Ribeifio Pre- to), and to Dr. Peter R. Moroko, for the stimulus and ex- pert research assistance during this study.

We also acknowledge the excellent work of Mrs. EdnCia F. Verceze in typing this manuscript.

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Cardiovascular Effects